Affinage

TSHR

Thyrotropin receptor · UniProt P16473

Length
764 aa
Mass
86.8 kDa
Annotated
2026-06-10
100 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/8 claims corpus-supported (88%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TSHR is a G protein-coupled receptor whose leucine-rich ectodomain binds TSH and patient autoantibodies to drive cAMP signaling in thyroid follicular cells, controlling thyroid hormone biosynthesis, iodide uptake, and proliferation (PMID:21247981, PMID:22898315). The canonical output couples through Gαs to cAMP, but receptor signaling is multiplexed: TSHR also engages Gαq and the Ras/MAPK pathway via Gβγ and PI3Kγ, and distinct loss-of-function mutations dissociate these arms (e.g., R450H selectively abrogates Gq while retaining partial Gs coupling) (PMID:11039907, PMID:21677043). Downstream of TSHR, GLIS3 is required for TSH-driven proliferation and hormone synthesis, directly binding the NIS and PDS iodide-transporter promoters and licensing mTORC1/RPS6 activation (PMID:29083325). Restoring TSHR in dedifferentiated thyroid carcinoma cells re-establishes iodide uptake and differentiation marker expression, while in thyroid cancer cells TSHR can instead couple to Gα12/13 to activate RhoA via LARG, producing a pro-migratory phenotype (PMID:34650915, PMID:22898315). Activating mutations across the transmembrane and intracellular domains cause constitutive cAMP signaling underlying toxic adenoma and non-autoimmune hyperthyroidism, whereas loss-of-function mutations reduce TSH binding and cAMP output (PMID:11039907, PMID:18727713, PMID:18694911, PMID:18306976, PMID:19158199). The receptor's structure and ligand pharmacology are defined: a 1.9 Å crystal structure shows the blocking autoantibody K1-70 clasping the LRD concave surface in roughly opposite orientation to stimulating antibodies, and a small-molecule agonist binds within the transmembrane helical bundle, explaining how agonists and antagonists act through distinct receptor surfaces (PMID:21247981, PMID:16488885, PMID:8100829). TSHR function is tuned by post-translational modification — N-glycosylation, sialylation, phosphorylation, palmitoylation, and dimerization with cleaved β-subunits all modulate surface expression and signaling (PMID:20719860, PMID:17524661, PMID:37827365). Extrathyroidally, TSHR is functionally expressed in orbital fibroblasts, adipocytes, hepatocytes, thymocytes, and immune cells, where it controls adipocyte differentiation and TSH-dependent lipolysis, hepatic lipid metabolism, orbital fibroblast proliferation and cytokine output, and tumor immune evasion through PKA/CREB- and JNK/c-JUN-driven checkpoint and PD-L1 induction (PMID:31622470, PMID:22289392, PMID:20152797, PMID:29421660, PMID:35101946, PMID:39285586).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1993 Medium

    Establishing how thyroid-stimulating versus blocking autoantibodies act resolved that the ectodomain carries distinct functional epitopes and that some antibodies block at a step downstream of TSH binding.

    Evidence Deletion/point mutagenesis with cAMP assays and patient immunoglobulin binding; antipeptide antibodies tested in cAMP, iodide uptake, and radioreceptor assays

    PMID:8100829 PMID:8103771

    Open questions at the time
    • Epitope maps inferred from mutant signaling, not structural complexes
    • Did not define the post-binding step blocked by downstream-acting antibodies
  2. 2000 Medium

    Constitutively activating carcinoma mutations were shown to be transforming, defining TSHR signaling as both cAMP/Gαs and Ras/MAPK driven via Gβγ and PI3Kγ.

    Evidence Stable expression of activating mutants in 3T3 cells with soft-agar, nude-mouse tumorigenesis, and pathway-inhibitor signaling assays

    PMID:11039907

    Open questions at the time
    • MAPK cascade components inferred pharmacologically
    • Did not establish relative contribution of each arm to transformation in human thyroid
  3. 2006 High

    Discovery of a transmembrane-binding small-molecule agonist established that TSHR can be activated through the helical bundle independent of the ectodomain.

    Evidence cAMP assays with TSHR/LHCGR chimeras, E3.37 mutagenesis, and 3D docking

    PMID:16488885

    Open questions at the time
    • Only partial agonism characterized
    • No experimental structure of the TMD-ligand complex
  4. 2007 Medium

    Characterization of post-translational modifications showed that sialylation, glycosylation, phosphorylation, dimerization, and lipid-raft localization tune receptor surface expression and signaling, including MAPK via GRKs/β-arrestins.

    Evidence Biochemical modification mutants, lipid-raft fractionation, and MAPK assays (review synthesizing primary data)

    PMID:17524661

    Open questions at the time
    • Review-level synthesis rather than a single primary dataset
    • Quantitative contribution of each modification to signaling not resolved
  5. 2008 Medium

    Functional reconstitution of disease mutations defined the genotype-function map: loss-of-function mutations abolish TSH binding and cAMP, while activating TM/intracellular mutations drive constitutive cAMP, including a first C-terminal germline activating mutation.

    Evidence Site-directed mutagenesis with 125I-TSH binding, cAMP and CRE-luciferase assays, surface-expression flow cytometry; family linkage analysis for Ile691Phe

    PMID:18306976 PMID:18694911 PMID:18727713

    Open questions at the time
    • Ile691Phe lacked in vitro functional confirmation
    • Surface vs. signaling defects not fully separated for all mutants
  6. 2009 High

    Dual-pathway assays demonstrated that individual mutations selectively impair Gs versus Gq coupling, showing TSHR signaling arms are genetically separable.

    Evidence In vitro mutant expression with cAMP (Gs) and IP1 (Gq) assays plus patient radioiodine correlation; cAMP characterization of additional loss-of-function mutants

    PMID:19158199 PMID:21677043

    Open questions at the time
    • Physiological consequence of Gq-selective loss not fully defined
    • No structural basis for differential coupling
  7. 2010 High

    Studies of β-subunit dimerization and adipocyte-specific knockout established negative regulation by cleaved ectodomain fragments and a dedicated TSH-dependent lipolytic role in adipose tissue.

    Evidence Co-IP, FRET, cAMP and surface-expression assays for β-subunit dimers; Fabp4-Cre conditional knockout with lipolysis assays

    PMID:20152797 PMID:20719860

    Open questions at the time
    • Source/regulation of β-subunit generation in vivo unclear
    • Downstream adipocyte lipolytic effectors not mapped
  8. 2012 Medium

    Extrathyroidal roles were extended: TSHR is required for adipocyte differentiation, restores differentiation/iodide uptake in dedifferentiated thyroid carcinoma, and amplifies PDGF-driven orbital fibroblast responses.

    Evidence siRNA knockdown in 3T3-L1 with adipogenic markers; TSHR transfection of dFTC-133 with radioiodine uptake; flow cytometry/ELISA with K1-70 and H89 blockade in orbital fibroblasts

    PMID:22289392 PMID:22438231 PMID:22898315

    Open questions at the time
    • Mechanism linking TSHR to PPAR-γ induction not defined
    • Redifferentiation durability and in vivo relevance untested
  9. 2015 Medium

    TSH/TSHR signaling was shown to suppress lipogenic FASN via PKA and ERK, and functional thymic TSHR expression was demonstrated, linking the receptor to adipocyte lipid metabolism and central immune tolerance.

    Evidence TSH stimulation of adipocytes with pathway inhibitors and FASN readouts; immunoblot, qPCR and functional TSAb stimulation of thymocytes; earlier allele-specific thymic transcript quantification

    PMID:15879364 PMID:21642385 PMID:25655684 PMID:25801430

    Open questions at the time
    • Causal link from thymic TSHR expression to tolerance not directly tested
    • Transcription factors mediating FASN suppression not identified
  10. 2017 High

    Genetic epistasis placed GLIS3 downstream of TSHR as a required effector for proliferation and hormone biosynthesis, providing a direct transcriptional link to iodide transporter genes.

    Evidence Conditional GLIS3 knockout mouse with ChIP-Seq, mTORC1/RPS6 signaling and proliferation assays

    PMID:29083325

    Open questions at the time
    • How TSHR/cAMP signaling activates GLIS3 not defined
    • GLIS3 role outside thyroid follicular cells untested
  11. 2018 Medium

    Liver-specific knockout established a hepatic TSHR role in triglyceride, cholesterol, and LDL metabolism, extending the receptor's lipid-regulatory function beyond adipose tissue.

    Evidence Liver-specific Cre/loxP knockout with hepatic/serum lipid measurement and metabolic chamber studies

    PMID:29421660

    Open questions at the time
    • Hepatic TSHR signaling pathway not mapped
    • Endogenous ligand driving hepatic signaling unclear
  12. 2019 Medium

    In orbital fibroblasts, TSHR activation was shown to drive proliferation through PI3K/Akt and a miR-146a/miR-155–ZNRF3/PTEN axis, defining a mechanism for orbital pathology.

    Evidence siRNA knockdown, BrdU proliferation, PI3K inhibitor, and miRNA/target qPCR

    PMID:31622470

    Open questions at the time
    • miRNA-target effects validated by expression, not direct repression assays in this system
    • Single cell-type model
  13. 2022 Medium

    TSHR was shown to signal noncanonically through Gα12/13–LARG–RhoA to drive tumor cell migration and through PKA–JNK–c-JUN to induce PD-L1, recasting the receptor as a driver of cancer aggressiveness and immune evasion.

    Evidence Transcriptomics, immunoblotting, cAMP/iodide/migration assays for Gα12/13/RhoA; transcriptomics, signaling and homograft TSHR-inhibitor experiments for PD-L1

    PMID:34650915 PMID:35101946

    Open questions at the time
    • Switch from Gαs to Gα12/13 coupling mechanism unresolved
    • Single-lab findings without independent replication
  14. 2024 Medium

    Conditional CD8+ T cell TSHR deletion demonstrated that TSHR signaling drives T cell exhaustion via PKA/CREB and that tumor exosomes deliver TSHR to T cells, establishing a tumor-immune mechanism.

    Evidence Conditional knockout, RNA-seq, ChIP, luciferase, flow cytometry and exosome isolation

    PMID:39285586

    Open questions at the time
    • Exosomal TSHR transfer mechanism in patients untested
    • Single tumor type (CRC) examined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TSHR dynamically partitions among Gαs, Gαq, Gα12/13 and β-arrestin outputs across thyroidal and extrathyroidal tissues, and how this is set by ligand identity and post-translational state, remains unresolved.
  • No unified structural model linking ligand binding to differential G-protein selection
  • Tissue-specific signaling bias not systematically mapped
  • Palmitoylation mechanism characterized only by inhibition, not direct biochemistry

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0001618 virus receptor activity 3 GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3
Partners
ARHGEF12GLIS3GNA12GNA13GNAQGNASTSH

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 Crystal structure of the TSHR extracellular leucine-rich domain (amino acids 22-260) bound to a blocking-type human monoclonal autoantibody (K1-70) was solved at 1.9 Å resolution. K1-70 Fab binds the concave surface of the TSHR LRD with a large interface (2565 Ų), and mutation of contact residues influenced K1-70 activity, confirming the binding detail. K1-70 binds more N-terminally on the TSHR concave surface than the stimulating autoantibody M22 or TSH, clasping the surface in approximately the opposite orientation (~155° rotation) to M22, which may underlie its antagonist versus agonist functional difference. X-ray crystallography at 1.9 Å; site-directed mutagenesis of interface residues; functional cAMP assays to validate structural contacts Journal of molecular endocrinology High 21247981
2006 A low molecular weight (LMW) thienopyrimidine agonist (org41841) acts as a partial agonist for TSHR by binding within the transmembrane domain rather than the ectodomain. 3D molecular modeling predicted a binding pocket in clefts between TMHs 3, 4, 5, 6, 7 and extracellular loop 2, and chimeric receptor signaling studies provided experimental support. A key interaction between the conserved negatively charged E3.37 in the transmembrane domain and the amino group of org41841 was experimentally confirmed by mutagenesis. cAMP signaling assays with chimeric TSHR/LHCGR receptors; site-directed mutagenesis of E3.37; 3D molecular modeling and ligand docking The Journal of biological chemistry High 16488885
2010 TSHR β-subunits (cleaved/truncated ectodomain fragments) dimerize with full-length TSHR, as demonstrated by co-immunoprecipitation and fluorescence resonance energy transfer. This interaction reduces full-length TSHR cell-surface expression and significantly decreases TSH-induced cAMP generation without altering basal constitutive cAMP levels. Truncated β-subunits also show faster internalization rates, contributing to reduced surface receptor availability and signaling. Co-immunoprecipitation; fluorescence resonance energy transfer (FRET); cAMP assays; flow cytometry for cell-surface expression Molecular endocrinology High 20719860
2000 Constitutively activating TSHR mutations (A623S and T632I) identified in thyroid carcinomas transform mouse 3T3 cells to a fully neoplastic phenotype (growth in soft agar; nude mouse tumorigenesis). The transformation is mediated by at least two pathways: the cAMP pathway via Gαs, and the Ras-dependent MAPK pathway via Gβγ and PI3Kγ. PI3Kγ signals to MAPK through a cascade involving a tyrosine kinase, Shc, Grb2, Sos, Ras, and Raf. Stable transfection of constitutively active TSHR mutants into 3T3 cells; soft agar colony formation; nude mouse tumor formation; pathway inhibitor experiments; signaling assays Oncogene Medium 11039907
2007 TSHR undergoes multiple post-translational modifications including N-glycosylation, phosphorylation, sialylation, and oligomerization/dimerization that modulate its function. Increased TSHR sialylation results in increased cell-surface expression. TSHR multimerization preferentially localizes in lipid rafts. In addition to coupling to Gαs and Gαq, TSHR also activates the MAPK pathway involving GRKs and β-arrestins. Biochemical characterization of glycosylation/sialylation mutants; lipid raft fractionation; MAPK pathway assays; review of multiple published studies Trends in endocrinology and metabolism Medium 17524661
2017 GLIS3 acts downstream of TSH/TSHR signaling and is required for TSH/TSHR-mediated proliferation of thyroid follicular cells and biosynthesis of thyroid hormone. GLIS3 deficiency blocks TSH-mediated activation of the mTORC1/RPS6 pathway and reduces expression of cell division genes. ChIP-Seq showed GLIS3 directly binds promoters of NIS and PDS iodide transporter genes required for thyroid hormone biosynthesis. Conditional GLIS3 knockout mouse model; ChIP-Seq; promoter analysis; mTORC1/RPS6 pathway signaling assays; cell proliferation assays The Journal of clinical investigation High 29083325
2019 TSHR activation by TSH in orbital fibroblasts stimulates proliferation through the PI3K/Akt signaling cascade and induces expression of miR-146a and miR-155. These microRNAs enhance proliferation by reducing expression of their targets ZNRF3 and PTEN, which normally limit cell proliferation. TSHR depletion by siRNA abrogated TSH-induced proliferation. TSHR-specific siRNA knockdown; BrdU incorporation proliferation assay; Western blot for PI3K/Akt activation; PI3K inhibitor (LY294002); qPCR for miRNA and gene expression Investigative ophthalmology & visual science Medium 31622470
2012 TSHR expression is required for adipocyte differentiation; knockdown of TSHR in 3T3-L1 preadipocytes blocks their differentiation into mature adipocytes as assessed by Oil-Red-O staining for lipid accumulation and reduced PPAR-γ and ALBP mRNA expression. TSHR siRNA knockdown in 3T3-L1 cells; Oil-Red-O staining; RT-PCR for adipogenic markers (PPAR-γ, ALBP) Lipids in health and disease Medium 22289392
2010 Tissue-specific knockout of TSHR in white adipose tissue (using Fabp4-Cre/loxP system) results in increased adipocyte size and decreased sensitivity to TSH-induced lipolysis (10-fold lower sensitivity to TSH in adipocytes from knockout mice). Catecholamine-induced lipolysis and insulin-mediated inhibition of lipolysis were unaltered, indicating TSHR specifically mediates TSH-dependent lipolytic signaling in adipocytes. Adipocyte-specific Cre-loxP conditional knockout; adipocyte size measurement; lipolysis assays with TSH, catecholamines, and insulin; thyroid gland histology Biochemical and biophysical research communications High 20152797
2018 Liver-specific TSHR knockout (LT-KO) mice show reduced hepatic triglyceride and cholesterol content due to modified synthesis and catabolism of lipids, and decreased serum LDL-C levels, establishing a role for hepatic TSHR in liver lipid metabolism. Systemic energy metabolism was not affected by hepatic TSHR deletion. Liver-specific conditional TSHR KO (Cre/LoxP); measurement of hepatic and serum lipid levels; metabolic chamber studies Biochemical and biophysical research communications Medium 29421660
2015 TSH/TSHR signaling suppresses fatty acid synthase (FASN) expression in mature adipocytes. TSH treatment activates PKA, phosphorylates CREB, and activates ERK1/2 and JNK. TSH-induced downregulation of FASN was partially abolished by PKA and ERK inhibition but not JNK inhibition, indicating FASN suppression is mediated by PKA and ERK pathways downstream of TSHR. TSH stimulation of mature adipocytes; Western blot for PKA activation, CREB phosphorylation, ERK and JNK; pathway inhibitors; RT-PCR and Western blot for FASN Journal of cellular physiology Medium 25655684
2022 In thyroid cancer cells, TSH binds TSHR coupled to Gα12/13 protein (rather than canonical GαS), which activates RhoA through interaction with leukemia-associated RhoA guanine exchange factor (LARG), leading to a pro-migration tumorigenic phenotype. PI3K/AKT/mTOR signaling enhances this noncanonical Gα12/13 pathway by increasing LARG levels, while simultaneously inhibiting GαS-dependent expression of thyroid-specific molecules and iodide uptake. Transcriptomic sequencing; Western blot for Gα12/13, RhoA, LARG, and downstream signals; cAMP assay; iodide uptake assay; migration assays Frontiers in oncology Medium 34650915
1993 Specific deletions (residues 295-306, 299-301, 387-395) and point mutations (Cys301Ser, Cys390Ser, Tyr385Phe, Tyr385Ala) in the TSHR extracellular domain markedly diminish the ability of the receptor to respond to blocking TSHRAbs but not stimulating TSHRAbs, mapping distinct epitopes for blocking versus stimulating autoantibodies. Three mutants (deletions of 295-306, 387-395, and C301S point mutation) were particularly useful for detecting stimulating TSHRAb activity in the presence of blocking antibodies. Site-directed mutagenesis and deletion constructs; cAMP assays in transfected cells; competitive binding assays with patient immunoglobulins The Journal of clinical endocrinology and metabolism Medium 8100829
1993 Antibodies directed against TSHR extracellular domain peptides block TSH-mediated activation of thyroid cells via two distinct mechanisms: one involving direct inhibition of TSH binding to the receptor (shown only by anti-ETSHR but not antipeptide antibodies in radioreceptor assay), and another involving a step downstream of TSH binding (shown by anti-peptide 3A and anti-2 antibodies blocking cAMP release and iodide uptake without inhibiting TSH binding). Antipeptide antibody characterization; cAMP release assay; iodide uptake assay; radioreceptor assay (RRA) for TSH binding inhibition The Journal of clinical endocrinology and metabolism Medium 8103771
2009 TSHR mutations R450H, T145I, and I661fs have distinct G-protein coupling defects. R450H-TSHR retains partial ability to transduce Gs-coupled signaling but has abrogated Gq-coupled signaling (dominant Gq coupling defect). T145I-TSHR retains partial ability to transduce both Gs and Gq pathways. I661fs-TSHR cannot transduce either Gs or Gq signaling. In vitro expression of mutant TSHR constructs; cAMP assay (Gs pathway); IP1/inositol phosphate assay (Gq pathway); phenotype correlation with radioiodine uptake in patients The Journal of clinical endocrinology and metabolism High 21677043
2005 Orbital fibroblasts undergoing adipocytic differentiation show increased TSHR mRNA and protein expression. Differentiated orbital fibroblasts respond functionally to bovine TSH with increased cAMP production; a thyroid-inhibiting antibody (TBAb) inhibited this cAMP response and a thyroid-stimulating antibody (TSAb) stimulated cAMP production, demonstrating that TSHR expressed on differentiated orbital fibroblasts is functionally active and responds to autoantibodies. Real-time PCR for TSHR mRNA; immunocytochemistry for TSHR protein; cAMP radioimmunoassay after TSH and antibody stimulation European journal of endocrinology Medium 15879364
2012 PDGF-AB and PDGF-BB (but not PDGF-AA) stimulation increases TSHR expression on orbital fibroblasts. This enhanced TSHR expression amplifies the response to TSHR-stimulating autoantibodies, increasing production of IL-6, IL-8, CCL2, and hyaluronan. These effects were blocked by a TSHR blocking antibody (K1-70) and a cAMP inhibitor (H89), confirming they are mediated through TSHR signaling and cAMP. Flow cytometry for TSHR expression; ELISA for cytokine and hyaluronan production; pharmacological blocking with K1-70 antibody and H89 cAMP inhibitor The Journal of clinical endocrinology and metabolism Medium 22438231
2022 TSH-TSHR signaling induces tumor PD-L1 expression through the TSHR-AC-PKA-JNK-c-JUN signaling pathway. TSHR inhibition reversed tumor immune evasion by inhibiting PD-L1 expression in tumor and myeloid cells and enhancing effector T cell activation in homograft mouse models. Transcriptomic sequencing; cellular signaling experiments; Western blot for pathway components; tumor immune evasion assays; homograft mouse model with TSHR inhibitor Journal for immunotherapy of cancer Medium 35101946
2024 TSHR signaling promotes CD8+ T cell exhaustion through the PKA/CREB signaling pathway, upregulating immune checkpoint receptors PD-1 and TIM3. Conditional deletion of TSHR in CD8+ tumor-infiltrating lymphocytes improved effector differentiation and suppressed checkpoint receptor expression. CRC cells were found to secrete TSHR via exosomes, increasing TSHR levels in CD8+ T cells to promote immunosuppression. Conditional TSHR deletion in CD8+ T cells; RNA-sequencing; Western blotting; chromatin immunoprecipitation; luciferase reporter assay; immunofluorescence and flow cytometry; exosome isolation Cancer communications Medium 39285586
2021 TSHR knockout or inhibition of palmitoylation-dependent TSHR activation alleviates TSH-induced apoptosis in Schwann cells exposed to high glucose/palmitic acid conditions. PA-induced TSHR palmitoylation was identified as a post-translational modification that enables TSH-mediated oxidative stress, mitochondrial dysfunction, and apoptosis in RSC96 Schwann cells. TSHR knockout in cell model; inhibition of TSHR palmitoylation; apoptosis assays; oxidative stress markers; mitochondrial function assays Oxidative medicine and cellular longevity Low 34804362
2008 TSHR loss-of-function mutations (E34K, D403N, M527T, R46P, W488R) reduce or abolish TSH binding capacity and cAMP production in response to TSH. R46P and W488R completely abrogate both TSH binding and cAMP response. P27T has reduced cAMP response only at the highest TSH dose and is likely a polymorphism rather than a pathogenic mutation. Site-directed mutagenesis; expression in COS cells; cAMP assay; 125I-TSH binding assay; microchip flow cytometry for cell-surface expression Clinical endocrinology Medium 18727713
2008 Novel activating TSHR mutations A623F and I635V in the transmembrane/intracellular domain cause constitutive activation of the cAMP pathway as demonstrated by elevated basal CRE-luciferase reporter activity in transfected cells compared to wild-type. This constitutive activation underlies toxic thyroid adenoma formation. Site-directed mutagenesis; CRE-luciferase reporter assay in transfected CO7 cells European journal of endocrinology Medium 18694911
2023 Perfluorooctanoic acid (PFOA) disrupts TSH-activated cAMP signaling in thyroid cells by inhibiting TSHR mRNA expression and impairing TSHR N-glycosylation, thereby reducing CREB phosphorylation and downstream thyroid-specific gene transcription. These effects were rescued by the adenylyl cyclase activator forskolin, confirming TSHR-proximal disruption. RT-PCR and Western blot for TSHR and downstream gene expression; cAMP assay; CREB phosphorylation by Western blot; ER stress markers; forskolin rescue experiment Environmental research Medium 37827365
2011 TSHR intron 1 disease-associated SNPs (rs179247 predisposing allele) lead to significantly reduced TSHR mRNA transcripts in thymus glands. Allele-specific transcript quantification in heterozygous individuals showed that the TSHR predisposing allele is expressed at lower levels than the protective allele in both thymic epithelial cells and thymocytes, suggesting that defective central T cell tolerance contributes to Graves' disease pathogenesis. Allele-specific transcript quantification by real-time PCR in thymic tissue; comparison of mRNA levels by genotype Human molecular genetics Medium 21642385
2015 TSHR is functionally expressed in thymocytes, and Graves' disease stimulating autoantibodies (TSAbs) can stimulate thymocytes through this receptor, as confirmed by protein immunoblotting, qPCR, and functional signaling assays. TSHR expression is confined to maturing thymocytes. Protein immunoblotting; quantitative PCR; functional thymic TSHR stimulation assays with TSAbs Journal of immunology Medium 25801430
2008 A novel germline activating TSHR mutation at codon 691 (Ile691Phe) located in the intracellular C-terminal domain causes autosomal dominant non-autoimmune hyperthyroidism across four generations. This is the first identified germline mutation in the intracellular C-terminal domain of TSHR. PCR sequencing of TSHR gene; linkage analysis to chromosome 14q24.2-31.3; in silico structural analysis Journal of human genetics Low 18306976
2009 In vitro characterization of TSHR mutations G132R, A204V, D403N, and R450H confirmed loss-of-function for all four. R450H showed a founder effect in Japanese patients, being present in 6 of 9 mutant alleles identified. In vitro expression of mutant TSHR; cAMP assay for functional characterization; PCR sequencing in patient cohort The Journal of clinical endocrinology and metabolism Medium 19158199
2012 TSHR gene transfection into dedifferentiated thyroid follicular carcinoma cells (dFTC-133) increased radioiodine uptake 2.9-fold and upregulated mRNA of thyroid differentiation markers NIS (4-fold), TPO (1.5-fold), Tg (2.2-fold), and TSHR itself (1.7-fold), demonstrating that TSHR expression is sufficient to promote redifferentiation and restore iodine uptake capacity. TSHR plasmid transfection; radioiodine (125I) uptake assay; real-time PCR for thyroid differentiation markers; immunofluorescence for TSHR localization Nuclear medicine and biology Medium 22898315

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 TSH-R expression and cytokine profile in orbital tissue of active vs. inactive Graves' ophthalmopathy patients. Clinical endocrinology 196 12608932
2015 A brain circuit that synchronizes growth and maturation revealed through Dilp8 binding to Lgr3. Science (New York, N.Y.) 141 26429885
2015 Drosophila Lgr3 Couples Organ Growth with Maturation and Ensures Developmental Stability. Current biology : CB 140 26441350
2005 Association of the TSHR gene with Graves' disease: the first disease specific locus. European journal of human genetics : EJHG 135 16106256
2015 Long noncoding RNA PVT1 modulates thyroid cancer cell proliferation by recruiting EZH2 and regulating thyroid-stimulating hormone receptor (TSHR). Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 133 26427660
2015 Dilp8 requires the neuronal relaxin receptor Lgr3 to couple growth to developmental timing. Nature communications 131 26510564
2004 Dry eye syndrome in thyroid-associated ophthalmopathy: lacrimal expression of TSH receptor suggests involvement of TSHR-specific autoantibodies. Acta ophthalmologica Scandinavica 129 15115450
2011 Crystal structure of the TSH receptor (TSHR) bound to a blocking-type TSHR autoantibody. Journal of molecular endocrinology 101 21247981
2009 Association of the thyroid stimulating hormone receptor gene (TSHR) with Graves' disease. Human molecular genetics 100 19244275
2007 Effects of serum TSH and FT4 levels and the TSHR-Asp727Glu polymorphism on bone: the Rotterdam Study. Clinical endocrinology 98 17803697
2015 Genetic predisposition to papillary thyroid carcinoma: involvement of FOXE1, TSHR, and a novel lincRNA gene, PTCSC2. The Journal of clinical endocrinology and metabolism 86 25303483
2012 Role of extrathyroidal TSHR expression in adipocyte differentiation and its association with obesity. Lipids in health and disease 84 22289392
2006 A low molecular weight agonist signals by binding to the transmembrane domain of thyroid-stimulating hormone receptor (TSHR) and luteinizing hormone/chorionic gonadotropin receptor (LHCGR). The Journal of biological chemistry 82 16488885
2009 TSHR mutations as a cause of congenital hypothyroidism in Japan: a population-based genetic epidemiology study. The Journal of clinical endocrinology and metabolism 77 19158199
2016 Growth Coordination During Drosophila melanogaster Imaginal Disc Regeneration Is Mediated by Signaling Through the Relaxin Receptor Lgr3 in the Prothoracic Gland. Genetics 71 27558136
2017 GLIS3 is indispensable for TSH/TSHR-dependent thyroid hormone biosynthesis and follicular cell proliferation. The Journal of clinical investigation 63 29083325
2019 TSHR Signaling Stimulates Proliferation Through PI3K/Akt and Induction of miR-146a and miR-155 in Thyroid Eye Disease Orbital Fibroblasts. Investigative ophthalmology & visual science 59 31622470
1994 Expression of thyrotropin receptor (TSH-R), thyroglobulin, thyroperoxidase, and calcitonin messenger ribonucleic acids in thyroid carcinomas: evidence of TSH-R gene transcript in medullary histotype. The Journal of clinical endocrinology and metabolism 59 8157713
2010 Genetic hyperthyroidism: hyperthyroidism due to activating TSHR mutations. European journal of endocrinology 58 20926595
2021 Tumour-derived Dilp8/INSL3 induces cancer anorexia by regulating feeding neuropeptides via Lgr3/8 in the brain. Nature cell biology 57 33558728
2011 Association of an SNP with intrathymic transcription of TSHR and Graves' disease: a role for defective thymic tolerance. Human molecular genetics 56 21642385
2009 Clinical associations of the genetic variants of CTLA-4, Tg, TSHR, PTPN22, PTPN12 and FCRL3 in patients with Graves' disease. Clinical endocrinology 55 19438904
2018 The biology and evolution of the Dilp8-Lgr3 pathway: A relaxin-like pathway coupling tissue growth and developmental timing control. Mechanisms of development 54 29715504
2010 Genetics of thyroid autoimmunity and the role of the TSHR. Molecular and cellular endocrinology 52 20083159
2022 TSH-TSHR axis promotes tumor immune evasion. Journal for immunotherapy of cancer 51 35101946
2008 Prevalence of mutations in TSHR, GNAS, PRKAR1A and RAS genes in a large series of toxic thyroid adenomas from Galicia, an iodine-deficient area in NW Spain. European journal of endocrinology 46 18694911
1993 Use of thyrotropin receptor (TSHR) mutants to detect stimulating TSHR antibodies in hypothyroid patients with idiopathic myxedema, who have blocking TSHR antibodies. The Journal of clinical endocrinology and metabolism 46 8100829
2010 Qualitative and quantitative promoter hypermethylation patterns of the P16, TSHR, RASSF1A and RARβ2 genes in papillary thyroid carcinoma. Medical oncology (Northwood, London, England) 44 20535589
2016 Sex-specific regulation of Lgr3 in Drosophila neurons. Proceedings of the National Academy of Sciences of the United States of America 43 26884206
2023 A review of TSHR- and IGF-1R-related pathogenesis and treatment of Graves' orbitopathy. Frontiers in immunology 41 36742308
2015 Mechanisms of Action of TSHR Autoantibodies. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 41 26361260
2010 Tissue-specific knockout of TSHr in white adipose tissue increases adipocyte size and decreases TSH-induced lipolysis. Biochemical and biophysical research communications 41 20152797
2022 CAR-T Cells Targeting TSHR Demonstrate Safety and Potent Preclinical Activity Against Differentiated Thyroid Cancer. The Journal of clinical endocrinology and metabolism 40 34751400
1993 Dual mechanism of perturbation of thyrotropin-mediated activation of thyroid cells by antibodies to the thyrotropin receptor (TSHR) and TSHR-derived peptides. The Journal of clinical endocrinology and metabolism 40 8103771
2016 A domestication related mutation in the thyroid stimulating hormone receptor gene (TSHR) modulates photoperiodic response and reproduction in chickens. General and comparative endocrinology 39 26873630
2012 PDGF enhances orbital fibroblast responses to TSHR stimulating autoantibodies in Graves' ophthalmopathy patients. The Journal of clinical endocrinology and metabolism 38 22438231
2005 Evidence for protein and mRNA TSHr expression in fibroblasts from patients with thyroid-associated ophthalmopathy (TAO) after adipocytic differentiation. European journal of endocrinology 36 15879364
2010 Thyroid stimulating hormone receptor (TSHR) intron 1 variants are major risk factors for Graves' disease in three European Caucasian cohorts. PloS one 33 21124799
2007 Modulation of TSHR signaling by posttranslational modifications. Trends in endocrinology and metabolism: TEM 33 17524661
2017 TSHR as a therapeutic target in Graves' disease. Expert opinion on therapeutic targets 32 28127991
2010 Novel TSHR mutations in consanguineous families with congenital nongoitrous hypothyroidism. Clinical endocrinology 32 20718767
2015 Genetics of Graves' Disease: Special Focus on the Role of TSHR Gene. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 31 26361261
2014 Epigenetic silencing of TSHR gene in thyroid cancer patients in relation to their BRAF V600E mutation status. Endocrine 31 24927793
2011 Molecular screening of the TSH receptor (TSHR) and thyroid peroxidase (TPO) genes in Korean patients with nonsyndromic congenital hypothyroidism. Clinical endocrinology 30 21707688
2024 Local TSH/TSHR signaling promotes CD8+ T cell exhaustion and immune evasion in colorectal carcinoma. Cancer communications (London, England) 29 39285586
2016 Next-generation sequencing analysis of TSHR in 384 Chinese subclinical congenital hypothyroidism (CH) and CH patients. Clinica chimica acta; international journal of clinical chemistry 27 27637299
1998 The formation of thyrotropin receptor (TSHR) antibodies in a Graves' animal model requires the N-terminal segment of the TSHR extracellular domain. Endocrinology 27 9528975
2021 TSH Combined with TSHR Aggravates Diabetic Peripheral Neuropathy by Promoting Oxidative Stress and Apoptosis in Schwann Cells. Oxidative medicine and cellular longevity 26 34804362
2011 Nonclassic TSH resistance: TSHR mutation carriers with discrepantly high thyroidal iodine uptake. The Journal of clinical endocrinology and metabolism 26 21677043
2012 TSHR is the main causative locus in autosomal recessively inherited thyroid dysgenesis. Journal of pediatric endocrinology & metabolism : JPEM 25 22876533
2015 Graves' disease TSHR-stimulating antibodies (TSAbs) induce the activation of immature thymocytes: a clue to the riddle of TSAbs generation? Journal of immunology (Baltimore, Md. : 1950) 24 25801430
2011 Small molecule TSHR agonists and antagonists. Annales d'endocrinologie 24 21511239
2018 Identification of Functional Thyroid Stimulating Hormone Receptor and TSHR Gene Mutations in Hepatocellular Carcinoma. Anticancer research 23 29715101
1996 Yersinia enterocolitica envelope proteins that are crossreactive with the thyrotropin receptor (TSHR) also have B-cell mitogenic activity. Journal of autoimmunity 23 8864826
2023 Perfluorooctanoic acid disrupts thyroid-specific genes expression and regulation via the TSH-TSHR signaling pathway in thyroid cells. Environmental research 22 37827365
2018 Analysis of chosen polymorphisms rs2476601 a/G - PTPN22, rs1990760 C/T - IFIH1, rs179247 a/G - TSHR in pathogenesis of autoimmune thyroid diseases in children. Autoimmunity 22 29973096
2013 Examination of orbital tissues in murine models of Graves' disease reveals expression of UCP-1 and the TSHR in retrobulbar adipose tissues. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 22 23386414
2019 Mutation screening of the TSHR gene in 220 Chinese patients with congenital hypothyroidism. Clinica chimica acta; international journal of clinical chemistry 21 31356790
2017 Next-generation sequencing of NKX2.1, FOXE1, PAX8, NKX2.5, and TSHR in 100 Chinese patients with congenital hypothyroidism and athyreosis. Clinica chimica acta; international journal of clinical chemistry 21 28455095
2017 Association between monoallelic TSHR mutations and congenital hypothyroidism: a statistical approach. European journal of endocrinology 21 29092890
2015 TSH/TSHR Signaling Suppresses Fatty Acid Synthase (FASN) Expression in Adipocytes. Journal of cellular physiology 21 25655684
2014 TSHR intronic polymorphisms (rs179247 and rs12885526) and their role in the susceptibility of the Brazilian population to Graves' disease and Graves' ophthalmopathy. Journal of endocrinological investigation 21 25543543
2012 A TSHr-LH/CGr chimera that measures functional TSAb in Graves' disease. The Journal of clinical endocrinology and metabolism 21 22496495
2017 Simultaneous induction of Graves' hyperthyroidism and Graves' ophthalmopathy by TSHR genetic immunization in BALB/c mice. PloS one 20 28319174
2012 Adoptive transfer of antithyrotropin receptor (TSHR) autoimmunity from TSHR knockout mice to athymic nude mice. Endocrinology 20 22334716
2014 Association between polymorphisms in the TSHR gene and Graves' orbitopathy. PloS one 19 25061884
2008 Functional studies of new TSH receptor (TSHr) mutations identified in patients affected by hypothyroidism or isolated hyperthyrotrophinaemia. Clinical endocrinology 19 18727713
2019 Regulation of TSHR Expression in the Thyroid and Thymus May Contribute to TSHR Tolerance Failure in Graves' Disease Patients via Two Distinct Mechanisms. Frontiers in immunology 17 31379878
2018 Liver-specific deletion of TSHR inhibits hepatic lipid accumulation in mice. Biochemical and biophysical research communications 17 29421660
2017 Downregulated expression of TSHR is associated with distant metastasis in thyroid cancer. Oncology letters 17 29344196
2015 Methylation status of TSHr in well-differentiated thyroid cancer by using cytologic material. BMC cancer 17 26519197
2010 Subunit interactions influence TSHR multimerization. Molecular endocrinology (Baltimore, Md.) 16 20719860
2000 Role of the cAMP and MAPK pathways in the transformation of mouse 3T3 fibroblasts by a TSHR gene constitutively activated by point mutation. Oncogene 16 11039907
2023 TSHR-based chimeric antigen receptor T cell specifically deplete auto-reactive B lymphocytes for treatment of autoimmune thyroid disease. International immunopharmacology 15 37690235
2016 TSHR Gene Polymorphisms in the Enhancer Regions Are Most Strongly Associated with the Development of Graves' Disease, Especially Intractable Disease, and of Hashimoto's Disease. Thyroid : official journal of the American Thyroid Association 15 27762730
2015 Mutations of TSHR and TP53 Genes in an Aggressive Clear Cell Follicular Carcinoma of the Thyroid. Endocrine pathology 15 26260781
2018 Association of BRAF gene and TSHR with cervical lymph node metastasis of papillary thyroid microcarcinoma. Oncology letters 14 30655754
2015 The Effect of a Mutation in the Thyroid Stimulating Hormone Receptor (TSHR) on Development, Behaviour and TH Levels in Domesticated Chickens. PloS one 14 26053744
2007 Preliminary evidence for interaction of PTPN12 polymorphism with TSHR genotype and association with Graves' ophthalmopathy. Clinical endocrinology 14 17608818
2023 Thyroid-stimulating hormone receptor (TSHR) as a target for imaging differentiated thyroid cancer. Surgery 13 37919223
2021 Crosstalk Between Abnormal TSHR Signaling Activation and PTEN/PI3K in the Dedifferentiation of Thyroid Cancer Cells. Frontiers in oncology 13 34650915
2018 Concurrent TSHR mutations and DIO2 T92A polymorphism result in abnormal thyroid hormone metabolism. Scientific reports 13 29973617
2008 A novel TSHR gene mutation (Ile691Phe) in a Chinese family causing autosomal dominant non-autoimmune hyperthyroidism. Journal of human genetics 13 18306976
2022 Capsaicin restores sodium iodine symporter-mediated radioiodine uptake through bypassing canonical TSH‒TSHR pathway in anaplastic thyroid carcinoma cells. Journal of molecular cell biology 12 34751390
2022 Sinomenine Hydrochloride Promotes TSHR-Dependent Redifferentiation in Papillary Thyroid Cancer. International journal of molecular sciences 12 36142613
2020 Association between TSHR gene methylation and papillary thyroid cancer: a meta-analysis. Endocrine 12 32279226
2014 A deletion including exon 2 of the TSHR gene is associated with thyroid dysgenesis and severe congenital hypothyroidism. Journal of pediatric endocrinology & metabolism : JPEM 12 24690939
1996 The gene for the thyrotropin receptor (TSHR) as a candidate gene for congenital hypothyroidism with thyroid dysgenesis. Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association 12 8981017
2021 Functional differences between TSHR alleles associate with variation in spawning season in Atlantic herring. Communications biology 11 34172814
2016 Upregulation of TSHR, TTF-1, and PAX8 in Nodular Goiter Is Associated with Iodine Deficiency in the Follicular Lumen. International journal of endocrinology 11 27525008
2014 Controversial constitutive TSHR activity: patients, physiology, and in vitro characterization. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 11 24845969
2010 Genetic defects, thyroid growth and malfunctions of the TSHR in pediatric patients. Frontiers in bioscience (Landmark edition) 11 20515734
2010 Current standards, variations, and pitfalls for the determination of constitutive TSHR activity in vitro. Methods in enzymology 11 21050930
2024 PET Imaging of Differentiated Thyroid Cancer with TSHR-Targeted [89Zr]Zr-TR1402. Molecular pharmaceutics 10 38976794
2017 The Role of Cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4) Gene, Thyroid Stimulating Hormone Receptor (TSHR) Gene and Regulatory T-cells as Risk Factors for Relapse in Patients with Graves Disease. Acta medica Indonesiana 10 29093229
2013 Epitope recognition in HLA-DR3 transgenic mice immunized to TSH-R protein or peptides. Endocrinology 10 23592747
2012 Re-induction of cell differentiation and (131)I uptake in dedifferentiated FTC-133 cell line by TSHR gene transfection. Nuclear medicine and biology 10 22898315
2024 Linsitinib inhibits proliferation and induces apoptosis of both IGF-1R and TSH-R expressing cells. Frontiers in immunology 9 39723207
2017 Novel germline mutation (Leu512Met) in the thyrotropin receptor gene (TSHR) leading to sporadic non-autoimmune hyperthyroidism. Journal of pediatric endocrinology & metabolism : JPEM 9 28195550
2015 Association between TSHR gene polymorphism and the risk of Graves' disease: a meta-analysis. Journal of biomedical research 9 27231040

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